The combining of two or more liquids together to a desired concentration and/or other characteristics, such as pH, viscosity or optical density, etc., of the constituent liquids is fundamental to many industrial processes and commercial products. This combining of liquids may be referred to as blending and is common in many industrial segments including pharmaceutical products, biopharmaceutical products, food and beverage processing products, household products, personal care products, petroleum products, chemical products and many other general industrial liquid products. In addition, blending systems find use in the field of liquid chromatography where blended liquids are provided to chromatography columns to permit the separation of mixtures for analysis or for purification purposes.
On site blending systems provide many advantages over purchasing pre-mixed chemicals. By using a blending system, a single barrel or feedstock concentrate produces many times its volume in diluted solution, depending on the desired concentration of the dilution. Thus, a single feedstock concentrate, used to produce the equivalent of many feedstocks of dilute liquid via, a blending system, greatly reduces, facility costs associated with fabrication of large tanks, floor space required, validation and quality control costs to confirm makeup, spoilage and disposal costs of non-compliant out of date or unused blended solutions. Freight costs associated with chemical delivery are also greatly reduced. In addition, onsite dilution and blending increases the variety of chemical concentrations and mixtures that are immediately available, without requiring a corresponding increase in the number, of feedstocks and chemicals that must be purchased, thereby reducing facility and operating costs and providing the logistical and administrative advantage of reduced inventory.
High accuracy in terms of concentration for blending systems providing liquids to liquid chromatography systems is vital. In addition, quality control concerns favor increased blending accuracy for liquids that are provided to industrial processes and that are used to create commercial products. Indeed, Six Sigma quality control principles dictate that lower variability in an industrial process results in a greater percentage of higher quality products being produced by the industrial process.
It is well known, however, that it is common for different levels of a large feedstock tank filled with a solution to have different proportionate mixtures of the constituent liquids. Gradients exist in large feedstocks in terms of both concentration and temperature. As a result, liquid provided from the feedstock will vary in terms of concentration posing challenges for accurate analysis, quality control analysis, as well as uniform delivery to a process. Feedstock solvents, commercially supplied, have variations in actual concentration from batch to batch as well as innate impurities preventing 100% pure concentrations from being available, in bulk supply.
FIG. 1 illustrates a prior art approach to blending a buffer or solvent solution with a diluting liquid such as water. Feedstocks, supplied from containers or tanks, are illustrated at 10a, 10b, 10c and 12. Feedstocks 10a through 10c contain different concentrations of buffer solution, for example, 0.1M, 0.5M and 1.0M buffer, respectively. Feedstock 12 contains water as a diluting liquid. It should be noted that feedstocks 10a, 10b and 10c could alternatively contain a solvent.
The system of FIG. 1 provides three blending modes, graphically illustrated at 14, 16 and 18. In the graphs illustrated at 14, 16 and 18, the x-axis represents time while the y-axis represents concentration. Graph 14 illustrates the isocratic blending mode where the buffer solution or solvent is provided to a process at a fixed concentration level or set point. Due to the inherent variability of feedstock 10a, the actual concentration delivered to the process, as illustrated at 14, will typically vary by ≧+/−2% from the set point/desired concentration.
Graph 16 of FIG. 1 illustrates the step gradient blending mode where the buffer solution is provided to the process at multiple concentration levels. In the example shown in FIG. 1, there are three concentration level steps, and thus, three set points. During the initial portion of buffer delivery, buffer of a lower concentration level is provided from feedstock 10a. After a period of time, the supply of buffer solution is switched from feedstock 10a to feedstock 10b so that a buffer solution having five times the concentration is provided. Finally, after a second period of time, the supply of buffer is switched from feedstock 10b to feedstock 10c so that a buffer solution having ten times the concentration (as compared to the buffer from feedstock 10a) is provided. As indicated at 16, such an approach passes on the innate feedstock variation of ≧+/−2% from the desired concentration levels.
Graph 18 in FIG. 1 illustrates the linear gradient blending mode where, for example, buffer solution or solvent from feedstock 10c is diluted with water from feedstock 12 so that the concentration of the buffer or solvent increases over time. In other words, the set point ramps up to a specified concentration level. As is known in the art, such blending is accomplished by adjusting the pumps or valves regulating the flow of liquid from feedstocks 10c and 12. While it is desired that the buffer concentration be increased linearly, as illustrated at 18, the resulting blend varies from the desired concentration by ≧+/−2% plus an additional variability of between +/−3% to +/−5%. In addition, due to the high variability, the buffer of feedstock 10c cannot be diluted with the water from feedstock 12 to accurately provide buffer having the concentrations of feedstocks 10a and 10b. The additional feedstocks 10a and 10b must be present in addition to feedstock 10c. In general, the variability indicated at 18 makes the linear gradient blending mode impractical for most applications.
As illustrated at 22 in FIG. 1, the variability for the three blending modes described above causes a variable and non-compliant product quality distribution. The graph 22 represents both the variability of the blend and the variability in product produced in processes relying on accurate blend makeup and delivery when the makeup blend is variable and inaccurate.
A wide range of products require pH adjustments. These include beverages, paints, specialty chemicals, cleaning solutions, buffers and chemically or biologically derived materials including various types of fermentation products, bioreactor products, cell cultures, recombinant expression systems and other natural source materials such as those with a therapeutic, nutritional or other application.
The standard prior art technique for pH adjustment uses a vessel, typically a 500 liter stainless steel or polymeric vessel or bag, containing the solution or product suspension to be adjusted. A pH probe is typically positioned at a port in the vessel wall. A mixer, such as a magnetic mixer or vortex/propeller mixer is usually inserted into the solution or product suspension in the vessel and used to facilitate the pH adjustment process. A pH adjusting solution is manually added to the vessel in portions while mixing occurs. After each manual addition, the solution or product suspension is given a few additional minutes to fully mix and then a few additional minutes for the pH reading to stabilize. The pH of the solution or product suspension is then read using the pH probe. The process is repeated with additional portions of the pH adjusting solution added until the desired pH level is reached.
The above prior art technique of pH adjustment suffers from a number of disadvantages. The process is manual and therefore does not permit automated control. Furthermore, if the desired pH set point is exceeded, the entire batch of solution or product suspension may be put at risk or even lost.
Another disadvantage of the prior art pH adjustment technique arises in the case of pH adjustment involving proteins or other labile materials. For example, when an acidic pH adjusting solution is added to the vessel, it may destroy the protein by hydrolyzing it at the point of contact with the protein in solution. As a result, the yields of protein are reduced and undesired hydrolyzed proteins become present in the product. This is particularly problematic when a very expensive protein, such as a therapeutic protein, is being treated.
A need has developed for a multi-stage blending system and method that provides accurate in-line blending of three or more liquid components. As an example, buffer make-up variability is a very significant contributor to variation in almost all production-scale pharmaceutical processes. This variation is proportional to the scale of an operation and is accepted in the industry as an inevitable consequence of large-scale blending and storage of liquid feedstock. When moving to large-scale tank-farms where thousands or even tens of thousands of liters of buffers are common, the challenges in removing concentration variations from buffers are quite large. As noted previously, on-site blending systems may be used to eliminate such batch-mode tank farms and the associated issues.
Furthermore, there is a demand for larger and larger volumes of dilute buffers for processes to meet increases in monoclonal antibody demand. Most facilities were not designed to accommodate the corresponding increase in buffer volume demand. While the implementation of in-line buffer dilution is a very attractive alternative to the traditional approach of making large volumes in batch mode, the process requires a dilute buffer which must meet not only a conductivity set point, but also a pH set point. A need therefore exists for a blending system and method that may accommodate arid simultaneously blend three liquid feed streams: (1) salt concentrate, (2) water and (3) acid/base modifier.
As another example, a purification process may require the accurate blending of three or more liquids, such as alcohol, salt solution and water. Such a system would need to control alcohol concentration and salt concentration based on conductivity. Such a process is especially important in oligonucleotide and peptide purification.